Targeting and activation of Rac1 are mediated by the exchange factor β-Pix

Rho guanosine triphosphatases (GTPases) are critical regulators of cytoskeletal dynamics and control complex functions such as cell adhesion, spreading, migration, and cell division. It is generally accepted that localized GTPase activation is required for the proper initiation of downstream signaling events, although the molecular mechanisms that control targeting of Rho GTPases are unknown. In this study, we show that the Rho GTPase Rac1, via a proline stretch in its COOH terminus, binds directly to the SH3 domain of the Cdc42/Rac activator β-Pix (p21-activated kinase [Pak]–interacting exchange factor). The interaction with β-Pix is nucleotide independent and is necessary and sufficient for Rac1 recruitment to membrane ruffles and to focal adhesions. In addition, the Rac1–β-Pix interaction is required for Rac1 activation by β-Pix as well as for Rac1-mediated spreading. Finally, using cells deficient for the β-Pix–binding kinase Pak1, we show that Pak1 regulates the Rac1–β-Pix interaction and controls cell spreading and adhesion-induced Rac1 activation. These data provide a model for the intracellular targeting and localized activation of Rac1 through its exchange factor β-Pix

Subjective Cognitive Dysfunction in Patients With and Without Fibromyalgia:Prevalence, Predictors, Correlates, and Consequences

Background: Subjective cognitive dysfunction (SCD) is common in fibromyalgia (FM), where it has been called 'fibrofog.' But its predictors and correlates are not well understood, including the extent to which SCD is present in fibromyalgia and non-fibromyalgia clinical populations. In addition, there are no studies available concerning SCD and fibromyalgia in the general population. We investigated these issues in a longitudinal rheumatic disease research databank and two cross-sectional general population studies. Methods: 11,150 unselected patients with rheumatoid arthritis completed an assessment of FM and cognitive severity (CS) status using the full 0-3 fibromyalgia 2016 criteria assessment. In addition, CS was dummy coded as present/absent (CS+). Assessments of SCD and fibromyalgia prevalence were available in two German general population studies. Results: Fibromyalgia was present (FM+) in 2,493 (21.7%) of clinical subjects and absent (FM-) in 9,017 (78.3%) by FM 2016 criteria. Cognitive severity was present in 1,304 (52.3%) of those with fibromyalgia and 1,009 (11.2%) of non-fibromyalgia subjects (FM-). In two general population studies, 42.0% to 52.3% of those with fibromyalgia were CS+ as were 1.4% to 5.5% of FM- subjects. Patients with CS+ had more abnormal scores for every measure of rheumatoid arthritis (RA) severity, fibromyalgia severity, and general health. The presence of CS+ was strongly related to somatic and non-somatic symptoms scores and less strongly to pain variables. The best predictor of CS+ in the clinic and the general population was the symptom severity scale (SSS), a criterion of fibromyalgia. Conclusions: Persons with SCD have high counts of somatic and psychological symptoms. Subjective cognitive dysfunction is best predicted by a simple symptoms score, and not by pain extent scores. Although SCD is called fibrofog in patients with FM, 43.6% of CS+ cases occurred in FM- subjects. Fibromyalgia and CS are correlated but appear to be different parts of a symptom severity continuum. 'Fibrofog' as a phenomenon linked only to fibromyalgia is a misnomer because it can be identified in many non-fibromyalgia patients as well

Measurement properties of physical function scales validated for use in patients with rheumatoid arthritis: A systematic review of the literature

Background:\ud The aim of this study was to systematically review the content validity and measurement properties of all physical function (PF) scales which are currently validated for use with patients with rheumatoid arthritis (RA). \ud \ud Methods:\ud Systematic literature searches were performed in the Scopus and PubMed databases to identify articles on the development or psychometric evaluation of PF scales for patients with RA. The content validity of included scales was evaluated by linking their items to the International Classification of Functioning Disability and Health (ICF). Furthermore, available evidence of the reliability, validity, responsiveness, and interpretability of the included scales was rated according to published quality criteria. \ud \ud Results:\ud The search identified 26 questionnaires with PF scales. Ten questionnaires were rated to have adequate content validity. Construct validity, internal consistency, test-retest reliability and responsiveness was rated favourably for respectively 15, 11, 5, and 6 of the investigated scales. Information about the absolute measurement error and minimal important change scores were rarely reported. \ud \ud Conclusion:\ud Based on this literature review, the disease-specificHAQ and the generic SF-36 can currently be most confidently recommended to measure PF in RA for most research purposes. The HAQ, however, was frequently associated with considerable ceiling effects while the SF-36 has limited content coverage. Alternative scales that might be better suited for specific research purposes are identified along with future directions for research

Efficacy and Safety of Methotrexate in Articular and Cutaneous Manifestations of systemic Lupus Erythematosus

Aim:  A prospective open-label study comparing the efficacy and safety of methotrexate (MTX) and chloroquine (CQ) in articular and cutaneous manifestations of systemic lupus erythematosus (SLE). Methods:  Consecutive SLE patients were randomly assigned to either 10 mg MTX weekly or 150 mg CQ daily during 24 weeks. Outcome measures were: numbers of swollen and tender joints, duration of morning stiffness, visual analog scale (VAS) for articular pain, physician global assessment index, patient global assessment index, SLE Disease Activity Index (SLEDAI), disappearance of skin rash and erythrocyte sedimentation rate (ESR). Results:  Forty-one patients consented to participate, 15 were allocated in the MTX group and 26 in the CQ group. Two patients on MTX dropped out due to side-effects and two in the CQ group, one due to side-effects and one due to inefficacy. Baseline demographic, clinical and laboratory parameters of the two groups were nearly identical. In both groups the clinical and laboratory parameters improved significantly over 24 weeks, except the ESR in the MTX group. The results of the outcome measures at the end of the trial did not differ significantly between the two groups, except morning stiffness (P < 0.05 in favor of the MTX group) and ESR (P < 0.01 in favor of the CQ group). Rise of serum alanine aminotransferase was observed in two cases in the MTX group and in none in the CQ group. Conclusion:  Low-dose MTX appears to be as effective as CQ in patients with articular and cutaneous manifestations of SLE, having an acceptable toxicity profile. Results of this prospective study need to be confirmed in a larger study

Further optimization of the reliability of the 28-joint disease activity score in patients with early rheumatoid arthritis

BACKGROUND: The 28-joint Disease Activity Score (DAS28) combines scores on a 28-tender and swollen joint count (TJC28 and SJC28), a patient-reported measure for general health (GH), and an inflammatory marker (either the erythrocyte sedimentation rate [ESR] or the C-reactive protein [CRP]) into a composite measure of disease activity in rheumatoid arthritis (RA). This study examined the reliability of the DAS28 in patients with early RA using principles from generalizability theory and evaluated whether it could be increased by adjusting individual DAS28 component weights. METHODS: Patients were drawn from the DREAM registry and classified into a "fast response" group (N = 466) and "slow response" group (N = 80), depending on their pace of reaching remission. Composite reliabilities of the DAS28-ESR and DAS28-CRP were determined with the individual components' reliability, weights, variances, error variances, correlations and covariances. Weight optimization was performed by minimizing the error variance of the index. RESULTS: Composite reliabilities of 0.85 and 0.86 were found for the DAS28-ESR and DAS28-CRP, respectively, and were approximately equal across patients groups. Component reliabilities, however, varied widely both within and between sub-groups, ranging from 0.614 for GH ("slow response" group) to 0.912 for ESR ("fast response" group). Weight optimization increased composite reliability even further. In the total and "fast response" groups, this was achieved mostly by decreasing the weight of the TJC28 and GH. In the "slow response" group, though, the weights of the TJC28 and SJC28 were increased, while those of the inflammatory markers and GH were substantially decreased. CONCLUSIONS: The DAS28-ESR and the DAS28-CRP are reliable instruments for assessing disease activity in early RA and reliability can be increased even further by adjusting component weights. Given the low reliability and weightings of the general health component across subgroups it is recommended to explore alternative patient-reported outcome measures for inclusion in the DAS28

Developing a patient satisfaction measure for imaging-based patient information during clinical consultations

Different types of medical imaging are increasingly being used to explain specific aspects of injuries to patients during consultations. However, there are no validated questionnaires available yet that specifically measure patients’ satisfaction with the use of such images. The objective of this study was to develop and evaluate a patient-centred measure of satisfaction with the use of medical imaging modalities in clinical treatment. A preliminary 22-item version of the Questionnaire for Patient Satisfaction with Imaging (QPSI) was developed based on extant literature and interviews with trauma patients. Final item selection and psychometric evaluations were conducted amongst a sample of 106 hospital trauma patients who were shown medical images of their injuries. The psychometric analyses resulted in a final 13-item questionnaire comprising two subscales that measure the importance of seeing the images (9 items) and the clearness of the image (4 items). Both subscales showed adequate internal consistency (α = 0.84 and 0.75). The subscales were weakly intercorrelated (ρ = 0.34) and were both significantly and independently associated with patients’ global ratings of satisfaction with the use of imaging. The final two-dimensional QPSI is an innovative, reliable and valid questionnaire for measuring patients’ satisfaction with imaging-based information during clinical consultations. Experience Framework This article is associated with the Quality & Clinical Excellence lens of The Beryl Institute Experience Framework (https://www.theberylinstitute.org/ExperienceFramework). Access other PXJ articles related to this lens. Access other resources related to this lens